Process for the cleavage of esters of 7-amino-cephem-4-carboxylic acid compounds

ABSTRACT

THE INVENTION CONCERNS THE CLEVAGE OF 2-IODOETHYL ESTERS OF 6-AMINO-PENAM-3-CARBOXYLIC ACID AND 7-AMINOCEPHEM-4-CARBOXYLIC ACID COMPOUNDS BY MEANS OF CHEMICAL REDUCING AGENTS. THE 2-IODOETHYL ESTERS AND THE CORRESPONDING 2-CHLORO- AND 2-BROMOETHYL ESTERS OF 6-AMINOPENAM-3-CARBOXYLIC ACID AND 7-AMINO-CEPHEM-4-CARBOXYLIC ACID COMPOUNDS ARE USEFUL FOR THE TEMPORARY PROTECTION OF THE CARBOXYL GROUP IN SUCH COMPOUNDS.

United States Patent Office 3,753,977. Patented Aug. 21, 1973 US. Cl. 260239.1 6 Claims ABSTRACT OF THE DISCLOSURE The invention concerns the cleavage of 2-iodoethyl esters of G-aminO-penam-3-carboxylic acid and 7-aminocephem-4-carboxylic acid compounds by means of chemical reducing agents. The 2-iodoethyl esters and the corresponding 2-chloroand Z-bromoethyl esters of G-aminopenam-3-carboxylic acid and 7-amino-cephem-4-carboxylic acid compounds are useful for the temporary protection of the carboxyl group in such compounds.

CROSS-REFERENCES TO RELATED APPLICATIONS This is a continuation-in-part of application Ser. No. 842,359, filed July 16, 1969.

BACKGROUND OF THE INVENTION It is known to protect temporarily the carboxylic acid group in compounds of the 6-amino-penam-3-carboxylic acid and 7aminocephem-4-carboxylic acid series by esterification with a 2,2,2-trichloroethyl group; the ester grouping can then be split by reduction under mild conditions (Woodward et al., J. Am. Chem. Soc., vol. 88, page 852 (1966)). The method for the temporary protection of a carboxyl group according to this process is generally applicable, but the yields are impaired by the formation of by-products, as well as by the relatively long duration of the reductive splitting of the ester. As byproducts the corresponding 2,2-dichloroethyl esters, which can only be split with difliculty under the mild conditions which are otherwise customary, are in particular formed apart from polar substances.

It has now been found that 6-amino-penam-3-carboxylic acid and 7-amino-cephem-4-carboxylic acid compounds of which the carboxyl groups are protected by temporary esterification, can be liberated under particularly favorable conditions from the corresponding 2-iodoethyl ester. At the same time it was found that on splitting the 2-iodoethyl ester, surprisingly no by-products are produced by dehalogenation and that the reductive splitting of the Z-iodoethyl ester takes place significantly more rapidly than that of the 2,2,2-trichloroethyl ester.

SUMMARY OF THE INVENTION Accordingly, the present invention relates to a process for the manufacture of 6-amino-penam-3carboxylic acid or of 7-amino-cephem-4-carboxylic acid compounds having free carboxyl groups from corresponding 6-aminopenam-3-carboxylic acid compounds or 7-amino-cephem- 4-carboxylic acid compounds protected by esterification, wherein Z-iodoethyl esters of 6amino-penam-3carboxylic acid or 7-amino-cephem-4-carboxylic acid compounds are treated with a chemical reducing agent.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In splitting the 2-iodoethyl ester of a 6-arnino-penam- 3-carboxylic acid compound or 7-amino-cephem-4-carboxylic acid compound by treatment with a chemical reducing agent, there are primarily used reducing metals or metal compounds, such as metal alloys or metal amalgams, advantageously in the presence of hydrogen-donating agents, which together with the metals, metal alloys or metal amalgams are capable of generating nascent hydrogen. Such reagents are especially zinc, as well as zinc alloys, for example, Zinc-copper, or zinc amalgam, which are advantageously used in the presence of acidic reagents, especially acids, optionally containing water, such as organic carboxylic, for example, lower alkanecarboxylic acids, such as acetic acid, for example, aqueous acetic acid, and also ammonium chloride or pyridine hydrochloride, or of alcohols, such as lower alkanols, optionally in the presence of an acid, as well as magnesium, furthermore alkali metal amalgams, for example, sodium or potassium amalgam, or aluminum amalgam, which are preferably used in the presence of a moist solvent, such as ether or lower alkanols, as well as strongly reducing metal salts, such as chromium-II salts, for example, chromium-II chloride or chromium-II acetate, which are preferably used in the presence of aqueous media containing organic solvents miscible with water, such as lower alkanols, lower alkanecarboxylic acid or ethers, for example, methanol, ethanol, acetic acid, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether.

The reaction is usually carried out in the presence of at least 1 mol of water and under mild conditions, for example, at room temperature or even while cooling, e.g. at temperatures of about l0 C. to about +30 C., if desired, in an inert gas atmosphere, such as a nitrogen atmosphere.

The 2-iodoethyl esters of 6-amino-penam-3carboxylic acid and 7-aminocephem-4-carboxylic acid compounds used according to the invention can be manufactured by forming the corresponding 2-X-ethyl ester in a 6-aminopenam-3-carboxylic acid or a 7-amino-cephem-4-carboxylic acid compound, with X representing primarily bromo, as well as chloro or iodo, and converting a resulting 2- chloroethyl or 2-bromoethyl ester into the 2-iodoethyl ester.

A 2-X-ethyl ester of 6-amino-penam-3-carboxylic acid or 7-amino-cephem-4-carboxylic acid compounds is formed according to methods which are in themselves known, wherein starting materials of the above type are usually employed, in which the amino group is protected, for example, by an acyl group. The 2-X-ethyl ester is, for example, obtained by the reaction with a Z-X-ethanol suitable for the esterification, especially the 2-chloroor 2-bromoethanol, in the presence of an esterifying agent, such as a carbodiimide, e.g. dicyclohexylcarbodiimide, as well as of carbonyldiimidazole, or according to any other known and suitable esterification process, such as reactiori of a salt of the acid with a reactive ester formed by the Z-X-ethanol with a strong inorganic acid or a strong organic sulfonic acid. Furthermore, acid halides, especially acid chlorides, as well as activated esters, such as, for example, esters with N-hydroxy-nitrogen compounds, or re active mixed anhydrides, for example, such as those formed with halogenoformic acid esters, such as lower alkyl, e.g. ethyl, chloroformate, or trichloroacetic acid, can be converted into 2-X-ethyl esters by reaction with the Z-X-ethanol, optionally in the presence of a base, such as pyridine.

In a Z-X-ethyl ester, wherein X represents chloro or bromo, the latter is replaced by iodo in a manner which is in itself known. Thus, for example, the 2-chloroethyl or Z-bromoethyl ester can be treated with a suitable iodine salt, especially an alkali metal iodide, such as sodium or lithium iodide, in the presence of a suitable solvent, especially an organic solvent, in which the iodine salt used, for example, sodium or lithium iodide, is easily soluble and the resulting bromine salt, for example, sodium bromide, is only sparingly soluble, primarily in the presence of acetone, ethyl methyl ketone, isopropyl methyl ketone or dimethylformamide, and the corresponding 2-iodoethyl ester is thus obtained.

Since the 2-X-ethyl ester grouping is extremely inert in behaviour towards the reagents usually employed in 6-amino-penam-3-carboxylic acid and 7-amino-cephem-4- carboxylic acid chemistry, except towards the reducing agents mentioned above, it is possible, using the temporary protection of the carboxylic acid in the form of a 2- X-ethyl ester, to carry out the most diverse reactions on the 6-amino-penam-3-carboxylic acid compounds and 7- amino-cephem-4-carboxylic acid compounds protected in this way, without the carboxyl group being involved or being very easily liberated from the protected carboxyl group.

Usually the reactions carried out on 6-amino-penam- S-carboxylic acid compounds and 7-amino-cephem-4-carboxylic acid compounds having a protected carboxyl group, such as splitting of a 6- or 7-N-acylamino group or rearrangement of penarn compounds into cephem compounds, is carried out with the 2-chloroethyl or 2-bromoethyl esters of 6-amino-penam-3-carboxylic acid compounds or 7'amino-cephem-4-carboxylic acid compounds and a 2-chloroor Z-bromoethyl ester is only converted into the corresponding 2-iodoethyl ester used according to the invention before splitting the ester grouping.

The 2-iodoethyl esters of 6-amino-penam-B-carboxylic acid compounds used in the process according to the invention are primarily 6-N-R-amino-2-R -2-R -penam-3- carboxylic acid 2-iodoethyl esters or l-oxides thereof, in which R represents hydrogen and above all an acyl group Ac, and each of the residues R and R represents an optionally substituted methyl group, while Z-iodoethyl esters of 7-amino-cephem-4-carboxylic acid compounds especially represent 7-N-R-amino-3-R -ceph(2)em-4-carboxylic acid Z-iodoethyl esters of 7-N-Ramino-3-R -ceph (3)em-4-carboxylic acid 2-iodoethyl esters, in which R and R have the abovementioned significance.

In the above compounds the group R primarily represents the acyl residue of an organic carboxylic acid, for example, a carbonic acid half-derivative or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclicaliphatic carboxylic acid.

Substituents of an optionally substituted methyl group R or R are primarily optionally functionally modified, such as etheri'fied or esterified, hydroxyl groups.

The acyl residue of a carbonic acid half-derivative is preferably the acyl residue of an appropriate half-ester, wherein the esterifying organic residue represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue or a heterocyclic-aliphatic residue, primarily the residue of an optionally substituted lower alkyl half-ester of carbonic acid (that is to say a lower alkoxy-carbonyl residue which is optionally substituted in the lower alkyl portion), as well as of a lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half-ester of carbonic acid which is optionally substituted in the lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl portion, respectively (that is to say a lower alkenyloxy-carbonyl, cycloalkoxy-carbonyl, phenyloxy-carbonyl or phenyl-lower alkoxy-carbony]. residue, which is optionally substituted in the lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl portion, respectively). Acyl residues of a carbonic acid half-ester are furthermore acyl residues of lower alkyl half-esters of carbonic acid, in which the lower alkyl portion contains as substituent a heterocyclic group, for example, one of the abovementioned heterocyclic groups of aromatic character, with the lower alkyl residue and the heterocyclic group optionally being substituted; such acyl residues are lower alkoxy-carbonyl groups, which contain an optionally substituted heterocyclic group of aromatic character in the lower alkyl portion.

The aliphatic residue, for example, in the acyl residue of aliphatic carboxylic acids, which also include formic acid, is an alkyl, alkenyl or alkinyl residue, especially a lower alkyl or lower alkenyl, as well as a lower alkinyl residue, which can, for example, contain up to 7, preferably up to 4, carbon atoms. Such residues may optionally be mono-, dior polysubstituted by functional groups, for example, by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylmercapto and optionally substituted phenylmercapto or phenyl-lower alkylmercapto, lower alkoxycarbonyloxy or lower alkanoyloxy group, or halogen atoms, as well as by nitro groups, optionally substituted amino groups, axido groups, oxo groups, acyl, such as lower alkanoyl or benzoyl groups, optionally substituted amino groups, azido groups, such as salified carboxyl groups, lower alkoxy-carbonyl groups, optionally N-substituted carbamoyl groups or cyano groups, and/or optionally functionally converted sulfo groups, such as sulfamoyl or salified sulfo group.

Cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon residues, for example, in the acyl residue of cycloaliphatic or cycloaliphatic-aliphatic carboxylic acids, are, for example, mono-, bior polycyclic cycloalkyl or cycloalkenyl groups, or cycloalkylor cycloalkenyl-lower alkyl or -lower alkenyl groups, wherein cycloalkyl residues, for example, contain up to 12, such as 3-8, preferably 3-6, ring carbon atoms, while cycloalkenyl residues, for example, possess up to 12, such as 3-8, especially 5-8, preferably 5 or 6, ring carbon atoms, as well as l to 2 double bonds, and the aliphatic portion of cycloaliphatic-aliphatic residues can, for example, contain up to 7, preferably up to 4, carbon atoms. The above cycloaliphatic or cycloaliphatic-aliphatic residues can, if desired, be mono-, dior polysubstituted, for example, by optionally substituted aliphatic hydrocarbon residues, such as, for example, the abovementioned optionally substituted lower alkyl groups, or, for example, like the above aliphatic hydrocarbon residues, by functional groups.

The aromatic hydrocarbon residue, for example, in the acyl residue of an aromatic carboxylic acid, is, for ex ample, a monoor bicyclic aromatic hydrocarbon residue, especially a phenyl residue, as well as a biphenyl or naphthyl residue, which can optionally be mono-, dior polysubstituted, for example, like the abovementioned aliphatic and cycloaliphatic hydrocarbon residues.

An araliphatic hydrocarbon residue, for example, in the acyl residue of an araliphatic carboxylic acid, is an optionally substituted aliphatic hydrocarbon residue which possesses, for example, up to three optionally substituted, monoor bicyclic, aromatic hydrocarbon residues, and primarily represents a phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkinyl residue, such residues containing 1-3 phenyl groups, being optionally mono-, dior polysubstituted in the aromatic and/or aliphatic portion, for example, like the abovementioned aliphatic and cycloaliphatic residues.

The heterocyclic portion of a heterocyclic or heterocyclic-aliphatic residue, for example, in the acyl residue of an appropriate carboxylic acid, is especially a monocyclic, as well as bicyclic or polycyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triazaor tetrazacyclic residue of aromatic character, which may optionally be mono-, dior polysubstituted, for example, like the abovementioned cycloaliphatic residues. The aliphatic portion in a heterocyclic-aliphatic residue can, for example, have the meaning given for the corresponding cycloaliphatic-aliphatic or araliphatic residues.

A hydroxyl group etherified by an optionally substituted aliphatic hydrocarbon residue is, for example, an alkoxy, as well as alkenyloxy or alkinyloxy, especially a lower alkoxy, as well as lower alkenyloxy or lower alkinyloxy group, wherein the organic residues of these groups can be mono-, dior polysubstituted, for example, like the abovementioned aliphatic hydrocarbon residues, by functional groups, such as free, etherified or esterified hydroxyl or mercapto groups, nitro groups, optionally substituted amino groups, optionally functionally modified carboxyl groups or acyl residues.

Etherified hydroxyl groups are, furthermore, optionally substituted phenyloxy, phenyl-lower alkoxy or phenyllower alkenyloxy groups, in which the hydrocarbon residues of hydroxyl groups etherified in this manner can be mono-, dior polysubstituted, for example, as indicated above, by hydrocarbon residues or functional groups.

A lower alkyl residue is, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-buty1 or tert. butyl, as well as n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl group, whilst a lower alkenyl residue can, for example, be a vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl group, and a lower alkinyl residue, for example, a propargyl or 2-butinyl group.

Optionally substituted aliphatic hydrocarbon residues, especially lower alkyl groups, which can, inter alia, also substitute cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic residues, contain, for example, the abovementioned substituents. Such substituted groups are, for example, hydroxy-lower alkyl or lower alkoxy-lower alkyl groups, especially halogeno-lower alkyl groups, such as monohalogeno-, dihalogenoor polyhalogeno-lower alkyl, e.g. -methyl, -ethyl or -1- or -2-propyl groups.

A cycloalkyl group is, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, as well as an adamantyl group, and a cycloalkenyl group is, for example, a 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl or 3-cycloheptenyl, as well as 2-cyclopropenyl group. A cycloalkyl-lower alkyl or cycloalkyl-lower alkenyl residue is, for example, a cyclopropyl-, cyclopentyl-, cyclohexylor cycloheptyl-methyl, -1,1- or -1,2-ethyl, -1,l-, -1,2- or -l,3-propyl, -vinyl or -allyl group, while a cycloalkenyl-lower alkyl or cycloalkenyl-lower alkenyl group, for example, represents a l-, 2- or 3-cyclopentenyl, l-, 2- or 3-cyclohexenyl or l-, 2- or 3-cycloheptenyl-methyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, -vinyl or -allyl group.

A naphthyl residue is a 1- or Z-naphthyl residue, while a biphenyl group is primarily a 4-biphenylyl group.

A phenyl-lower alkyl or phenyl-lower alkenyl residue is, for example, a benzyl, 1- or Z-phenylethyl, 1-, 2- or 3-phenyl-propy1, diphenylmethyl, trityl, 1- or Z-naphthylmethyl, styryl or cinnamyl residue.

A lower alkylene or lower alkenylene residue is, for example, represented by a 1,2-ethylene, 1,3-propylene, 2,2- dimethyl-l,3-propylene, 1,4-butylene, 1- or 2-methyl-l,4- butylene, 1,4-dimethyl-1,4-butylene, 1,5-pentylene, 1-, 2- or 3-methyl-1,5-pentylene, 1,6-hexylene, 2-buten-l,4-ylene or 2- or 3-penten-l,5-ylene group.

Heterocyclic residues of aromatic character are, for example, monocyclic monoaza-, monothiaor monooxacyclic residues of aromatic character, such as pyridyl, e.g. 2-, 3- or 4-pyridyl residues, thienyl, e.g. Z-thienyl residues, or furyl, e.g. 2-furyl residues, or bicyclic monoazacyclic residues of aromatic character, such as quinolinyl, e.g. 2- quinolinyl or 4-quinolinyl residues, or isoquinolinyl, e.g. l-isoquinolinyl residues, or monocyclic diaza-, triaza-, tetraza-, thiazaor oxazacyclic residues of aromatic character, such as pyrimidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl residues. Heterocyclicaliphatic residues are lower alkyl or lower alkenyl residues containing heterocyclic residues, for example, those mentioned above.

' Amongst etherified hydroxyl groups there should primarily be mentioned lower alkoxy groups, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, s'ec.-butyloxy, tert.-butyloxy, n-pentyloxy or tert.-pentyloxy groups, as well as substituted lower alkoxy groups, such as halogeno-lower alkoxy, especially Z-halogeno-lower alkoxy, e.g. 2,2,2-trichloroethoxy or 2-iodoethoxy groups, and also lower alkenyloxy, for example, vinyloxy or allyloxy groups, lower alkylenedioxy, for example, methylenedioxy or ethylenedioxy, as well as isopropylidenedioxy groups, phenyloxy groups, or phenyl-lower alkoxy, for example, benzyloxy or lor 2-phenylethyloxy groups, or lower alkoxy groups substituted by monocyclic monoaza-, monooxaor monothiacyclic groups of aromatic character, such as pyridyl-lower alkoxy, e.g. 2-pyridylmethoxy groups, furyl-lower alkoxy, e.g. furfuryloxy groups, or thienyl-lower alkoxy, e.g. 2-thenyloxy groups.

Etherified mercapto groups are lower alkylmercapto, for example methylmercapto or ethylmercapto groups, phenyl-mercapto groups or phenyl-lower alkylmercapto, for example, benzylmercapto groups.

Esterified hydroxyl groups are primarily halogen atoms, for example, fluorine, chlorine, bromine or iodine atoms, as well as lower alkanoyloxy, for example acetyloxy or propionyloxy groups.

Substituted amino groups are monoor disubstituted amino groups which primarily contain as substituents optionally substituted monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residues, as well as acyl groups. Such amino groups are especially lower alkylamino or di-lower alkylamino, for example, methylamino, ethylamino, dimethylamino or diethylamino groups, or lower alkyleneamino groups which are optionally interrupted by heteroatoms, such as oxygen or sulfur atoms, as well as nitrogen atoms optionally substituted, e.g. by lower alkyl groups, such as pyrrolidino, piperidino, morpholino, thiomorpholino or 4-methyl-piperazino groups, and also acylamino groups, especially lower alkanoylamino, such as acetylamino or propionylamino groups, or an optionally salified sulfoamino, such as a sulfoamino group in alkali metal, e.g. sodium, or ammonium salt form.

A lower alkanoyl residue is, for example, an acetyl or propionyl group.

A salified carboxyl group is, for example, a carboxyl group in an alkali metal or an ammonium salt form.

A lower alkoxy-carbonyl residue is, for example, a methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, tert.-butyloxycarbonyl or tert.-pentyloxycarbonyl group.

Optionally N-substituted carbamoyl groups are, for example, N-lower alkyl-carbamoyl or N,N-di-lower alkylcarbamoyl, such as N-methyl-, N-ethyl-, N,N-dimethylor N,N-diethyl-carbamoyl groups.

A lower alkenyloxy-carbonyl residue is, for example, the vinyloxy-carbonyl group, while cycloalkoxy-carbonyl and phenyl-lower alkoxy-carbonyl groups, in which the cycloalkyl or phenyl-lower alkyl residue have the abovementioned meaning, represent, for example, adamantyloxy-carbonyl or benzyloxy-carbonyl, diphenylmethoxycarbonyl or a-4-biphenylyl a methyl-ethoxy-carbonyl groups. Lower alkoxy-carbonyl groups, in which the lower alkyl residue is substituted by monocyclic, monoaza-, monooxaor monothiacyclic groups are, for example, furyl-lower alkoxy-carbonyl, such as furfuryloxy-carbonyl groups, or thienyl-lower alkoxy-carbonyl groups, for example, Z-thenyloxy-carbonyl groups.

The 2-iodoethyl esters of 6-amino-penam-3-carboxylic acid compounds and 7-amino-cephem-4-carboxylic acid compounds used in the process of the invention are primarily 6-N-R'-amino 2,2 dimethyl-penam-3-carboxylic acid 2-iodoethyl esters or l-oxides thereof, as Well as 7- N-R'-amino-3-R,,-methyl ceph (2)em-4-carboxylic acid 2-iodoethyl esters or 7 -N-R'-amino-R -methyl-ceph(3 em- "synthetically obtainable inclusive) N-acyl derivativesqf a 'fisamino-penicillanic acid compound or 7 -amino-cephalo- ,fsporanie acid compound,or the acyl residue of acarbon c acid half-estericapable of being easily split OifQandRg,

stands for: hydrogen or a hydroxy, lower alkq Y, F W

alkanoyloxy,e.g. acetyloxy group. I

The acyl residue in a pharmacologicallyactive N-acyl derivative of 6-amino-penicillanic acid or 7-aminc -cephalosporanic' acid is in the first place a group pip ng f .RI-( il)u(. li r i vRv-x in which fri represents" 0 and R stands 'forfan optionally substituted cycloaliphatic or aromatichydrocarbo'n residueor' a'n'op'tio'nally substituted heterocyclic residue, pref erably-ofaromatic character," a functionally converted, preferably etherified, hydroxy or mercapto" group, or an optionally substituted amino group, or wherein n represents 1, R stands for hydrogen or an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon residue or an optionally substituted heterocyclic residue, preferably of aromatic character, an optionally functionally converted, preferably etherified or esterified, hydroxy or mercapto group, an optionally functionally converted carboxyl group, an acyl group, an optionally substituted amino group or an azido group, and each of the residues R and R stands for hydrogen, or in which n represents 1, R stands for an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon residue or an optionally substituted heterocyclic residue, preferably of aromatic character, R represents an optionally functionally converted, preferably etherified, hydroxy or mercapto group, an optionally substituted amino group or an optionally functionally converted carboxyl group, and R stands for hydrogen, or in which n represents 1, each, of the residues R and R stands for a functionally converted, preferably etherified or esterified hydroxy group or an optionally functionally converted carboxyl group, and'R represents hydrogen, or in which n represents 1, R stands for hydrogen or an optionally substituted aliphatic hydrocarbon residue, and R and R together standfor an optionally substituted aliphatic hydrocarbon residue which is linked to the carbonatom by a'double' bond, or wherein n' represents Land R stands for an optionally s'ubstituted aliphatic, cycloaliphatic or aromatic hydrocarbon residue or'adoptionally substituted heterocyclic residue, preferably of aromatic character, R3 represents an op tionally substituted aliphatic or aromatic hydrocarbon-residue, and Rm stands for hydrogen or an optionally substi tuted aliphatic or aromatic hydrocarbon residue.

In the above definitionsfian aliphatic hydrocarbon residue means, for example, a linear or branched lower alkyl group, as Well aslower alkenyl or loweralkinyl group. Such a'residue, especially a lower alkyl residue, may contain as substituents, for example, optionally sub,- stituted cycloaliphatic or aromatic hydrocarbon residues, such as optionally substituted phenyl residues, or optionally substituted heterocyclic residues, preferably of aromatic character, furthermore optionally functionally converted, preferably etherified oresterifi'ed, hydroxy or mercapto groups, such as hydroxy or mercapto groups etherified by optionallysubstituted aliphatic, aromatic or araliphatic hydrocarbon residues, or by heterocyclic or heterocyclic-aliphatic groups, such as optionally subnew 8 loweralkanoyl or benzoyl residues, or optionally functionally convertedcarboxyl groups, such as loweralkoxycarbonyl,"carbamoyl or cyano groups, azido groups or optionallyjunctioually converted sulfojgroups', such as sulfamoyl groups. f i t A" cyt'zloaliphatic hydrocarbonresidue preferably contains 397 ringjcarbon atoms and is a cyeloalkyl oreyclog alkenyl groupi optionallyfsubstituted, for example, by

, aliphatic residues or substituted as the above aliphatic residue, and primarily containing 5 or6' ring carbon st ms." Preferably, such a cycloaliphatic, primarily cycloalkyl residue, contains" as'substituent an amino group in l-position.

The aforementioned aromatic hydrocarbon residues are in particulanoptionally substituted bicyclic, above all nionocy'clic aromatic hydrocarbon residues, which may bel' pa'rtially saturated, such'as naphthyl or tetrahydroiiaphthyLprimarily phenyl residues. These residues may 7 besub'stituted, for-example, by optionally substituted .ali-

phati'c,.cycl'oaliphatic or aromatic hydrocarbon groups, such as lower alkyl, trifiuoromethyl or optionally substitutedfcycloalkyl 0r phenylv residues, orby functional groups, such as optionally functionally converted hydroxy or mercapto groups, for example, etherified or ,esterified hydroxy or mercapto groups, such as those mentioned above, optionally functionally converted, such as etherified or esterified hydroxy or mercapto groups, nitro groups, optionally'substituted, amino groups, for example, the aforementioned amino groups, acylgroups, for example, theaforementioned-acyl residues, optionally functionally converted carboxyl groups, for example, the aforemen tioned groups of this kind, or optionally functionally converted sulfo groups, for example, the aforementioned sulfo residues. 1

An optionally substituted heterocyclic residue, preferably of aromatic character, is primarilya monocyclic monoaza-, monothia-, monooxa-,jdiaza-,.oxaza-, thiaza-, triazawor 'tetrazacyclic residue, preferably of aromatic character, for example, a pyridyLlpyridinium, thienyl, furyl, .iinidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl or tetrazolyl residue which may be substituted, for example,.as one of the aforementionediaromatic residues. vAn etherified ,hydroxy or mercapto group contains as an etherified residu e, for example, an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon residue, and is, for example, an optionally substituted lower alkoxy, lower 'alkenyloxy, phenyloxy, plienyl-lower alkoxy, lower alkyl-mercapto, lower alkenylmercapto, phenyl-mercapto or phenyl-lower alkyl-mercapto group. Other groups occurring in etherified hydroxy, especially in etherified mercapto groups are optionally substituted heterocyclic groups, preferably of aromatic character, such as, .for example, the aforementioned heterocyclic residues.

Esterified hydroxy groups .are, for example, hydroxy groups e sterified by inorganic or organic acids, especially halogen atoms, and also optionally substituted lower alkanoyloxy or benzoyloxy groups.

. Substituted amino groups contain as substituents one or two, optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon residues, it being possible for those residues, especially the aliphatic residues,- to be divalent; Such amino groups are, for example, lower 'alkylor di-lower alkylamino groups optionally substituted, e.g. by halogen atoms, or optionally substituted lower alkylene-amino groups having 5-7 ring members, in which the carbon atoms of the lower alkylene residue may be interrupted by an oxygen or sulfur atom or by a nitrogen atom which may be substituent, for example, by a lower alkyl group.

a An optionally functionally convertedcarboxy group is, forexample, an esterifiedv or amidated carboxyl group, such as a lower alkoxycarbonyl or an optionally Nsubstituted, such as N-lower alkylor N,N-di-lower alkylcarbamoyl groups, or a cyano group.

An acyl group is, for example, an optionally substituted lower alkanoyl, lower alkenoyl or benzoyl group.

In the aforementioned functional groups that are substituted by organic residues, such as etherified hydroxy or mercapto groups or substituted amino groups, the organic residues, for example, the aliphatic, cycloaliphatic or aromatic groups, also heterocyclic rseidues, may optionally be substituted, for example, as the aforementioned residues of this kind.

In the aforementioned acyl groups of the Formula I, n represents for example for O, and R stands for a cycloalkyl group having -7 ring carbon atoms, optionally substituted, preferably in l-position, by an amino or by a sulfoamino group, optionally present in salified form, for example, in the form of an alkali metal salt, for a phenyl, naphthyl or tetrahydronaphthyl group which may optionally be substituted, preferably by lower alkoxy, for a heterocyclic group optionally substituted, for example, by a lower alkyl and/ or phenyl group which itself may carry a substituent, such as halogeno, e.g. chloro, such as a 4-isoxazolyl group, or an amino group N-substituted by a lower alkyl residue optionally substituted by halogeno, e.g. chloro, or n represents '1, R stands for a lower alkyl group which may be substituted, preferably by halogeno, such as chloro, optionally substituted phenyloxy, amino and/or carboxy, for a lower alkenyl group, for a phenyl group which may be substituted, for example, by hydroxy, halogeno, e.g. chloro, or optionally substituted phenyloxy, for a pyridyl, pyridinium, thienyl, l-imidazolyl or l-tetrazolyl group which may be substituted, for example, by amino, for an optionally substituted lower alkoxy or phenyloxy group, for a lower alkyl-mercapto or lower alkenylmercapto group, for a phenyl-mercapto, Z-imidazolylmercapto or 1,2,4-triazol-3-yl-mercapto group which may be substituted, for example, by lower alkyl, halogeno, especially chloro or bromo, for a carboxy, lower alkoxycarbonyl or cyano group or for a carbamoyl group which latter may be N-substituted lower alkanoyl or benzyl group, or for an azido group, and R and R each represents hydrogen, or n represents 1, R stands for an optionally substituted phenyl or thienyl group, R for an amino or cyano group, or a carboxyl or sulfoarnino group present in salified form, for example, in the form of an alkali metal salt, or for an optionally substituted lower alkoxy or phenyloxy group, and R stands for hydrogen, or n represents 1, R and R each stands for a halo gen, e.g. bromine atom, or a lower alkoxy-carbonyl, e.g. methoxycarboxyl group, and R represents hydrogen, or n represents 1, and each of the groups R R and R stands for a lower alkyl group.

The above acyl groups may be represented, for example, by the residue of the formula in which m stands for 0, -1 or 2, preferably l1, and in which a carbon atom of a preferably unbranched alkylene residue of the formula (C H may be substituted, for example, by an optionally substituted amino group, a free, etherified or esterified hydroxy or mercapto group, a free or functionally converted carboxyl group or an oxo group, for example, by one of the abovementioned groups of this kind, and in which Y stands for an aromatic or cycloaliphatic hydrocarbon residue, such as a phenyl or cycloalkyl residue which may be substituted in the nucleus, for example, as the above alkylene residue, as well as by nitro or optionally functionally converted sulfo groups, or a heterocyclic group, preferably of aromatic character, which may be substituted, for example, as the above aromatic or cycloaliphatic residue, such as an optionally substituted pyridyl, pyridinium, thienyl, furyl, imidazolyl, tetrazolyl or isoxazolyl group, furthermore, a hydroxy or mercapto group etherified by an aromatic or cycloaliphatic hydrocarbon residue or by a heterocyclic residue, for example, of aromatic character, which residues may be substituted as indicated. Such acyl residues are, for

example, 2,6-dimethoxylbenzoyl, tetrahydronaphthoyl, 2- methoxy-naphthoyl, Z-ethoxy-naphthoyl, cyclopentylcarbonyl, ot-amino-cyclopentylcarbonyl or a-amino-cyclohexylcarbonyl (optionally with substituted amino group, for example, an optionally salified sulfoamino group) benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 2-phenyl-5- methyl-4-isoxazolylcarbonyl, 2-(2-chlorophenyl)-5-methyl-4-isoxazolylcarbonyl, 2- 2,6-dichlorophenyl) -5-methyl- 4-isoxazolylcarbonyl, phenylacetyl, phenacylcarbonyl, phenyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, Z-phenyloxypropionyl, a-phenyloxyphenylacetyl, amethoxy-phenylacetyl, ot-ethoxy-phenylacetyl, a-methoxy- 3,4-dichlorophenylacetyl, u-cyano-phenylacetyl, phenylglycyl (optionally with substituted amino group, such as a sulfoamino group which latter may be salified), benzylthioacetyl, benzylthiopropionyl, rx-carboxyphenylacetyl (optionally with a functionally converted carboxyl group, such as a salified carboxyl group), 2-pyridylacetyl, 4- amino-pyridinium-acetyl, Z-thienylacetyl, oc-CfifbOXY-Z-thienylacetyl or ot-carboxyl-3-thienylacetyl (optionally with a functionally converted carboxyl group which may be salified), a-cyano-2-thienylacetyl, u-amino-2-thienylacetyl or u-amino-3-thienylacetyl (optionally with a substituted amino, such as a sulfoamino group which latter may be salified), 3-thienylacetyl, Z-furylacetyl, l-imidazolylacetyl, 1-methyl-S-tetrazolylacetyl, 3-methyl-2-imidazolylthioacetyl or 1,2,4-triazol-3-yl-thioacetyl group. An acyl residue is, for example, also a group of the formula C H C(=O) or C H -C(=O)-, in which n stands for a whole number up to 7 and the chain may be straight or branched and/or optionally interrupted by an oxygen atom or sulfur atom and/or substituted, for example, by halogen atoms, free or functionally converted carboxyl groups, such as lower alkoxy-carbonyl or cyano groups, free or substituted amino groups, or 0x0, azido or nitro groups, for example, a propionyl, butyryl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, Z-pentenoyl, methoxyacetyl, methylthioacetyl, butylthioacetyl, allylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl, 5- amino-5-carboxy-valeryl (optionally with substituted amino and/or optionally functionally converted carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bismethoxycarbonylacetyl, N- phenylcarbamoylacetyl, cyanoacetyl, u-cyanopropionyl or 2-cyano-3-dimethylacrylyl group, furthermore a residue of the formula ZNHCO, in which Z represents an optionally substituted aromatic or aliphtic hydrocarbon residue, especially a lower alkyl residue, which is optionally substituted, preferably by lower alkoxy groups and/or halogen atoms, for example, the N-Z-chloroethylcarbamoyl residue.

A readily eliminable acyl residue is in the first place an acyl residue of a semi-ester of carbonic acid, which can be split off by reduction, for example, by treatment with a chemical reducing agent or with an acid, for example, trifiuoroacetic acid, such as a preferably multibranched or halogeno-substituted lower alkoxy-carbonyl residue, for example, a tert.-butyloxycarbonyl, tert.-pentyloxycarbonyl, 2,2,Z-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl residue or a residue capable of being converted into the latter, such as the Z-bromoethoxycarbonyl residue, a preferably polycyclic cycloalkoxycarbonyl, for example, adamantyloxycarbonyl residue, a phenyl-lower alkoxy-carbonyl residue, primarily an a-phenyl-lower alkoxy-carbonyl residue, in which the OL-pOSitlOn is preferably multi-substituted, for example, the diphenylmethoxycarbonyl or a-4-biphenyl-u-methylethoxycarbonyl residue, or a furyl-lower alkoxy-carbonyl residue, in the first place an wfuryl-lower alkoxy-carbonyl, such as furfuryloxycarbonyl residue.

Preferred as starting materials are 6-N-R"-amino-2,2- dimethyl-penam-3-carboxylic acid 2-iodoethyl esters or l-oxides thereof, or 7-N-R"-amino-3-R,,'-methyl-ceph(2) em-4-carboxylic acid 2-iodoethyl esters of 7-N-R-amino- 3-R '-carboxylic acid 2-iodoethyl esters, in which R" is hydrogen or the acyl residue of a naturally occurring or biosynthetically producible N-acyl derivatives of 6-amino penam-3-carboxylic acid or 7-amino-ceph(3)em-4-carboxylic acid compounds, such as an optionally substituted phenylacetyl or phenyloxyacetyl residue, furthermore an optionally substituted lower alkanoyl or lower alke'noyl residue, for example, the 4-hydroxy-phenylacetyl, hexa noyl, octanoyl, 3-hexenoyl, S-amino--carboxy-valeryl, nbutylmercaptoacetyl or allylmercaptoacetyl, and especial ly the phenylacetyl or phenyloxyacetyl residue, the acyl residue occurring in highly active N-acyl derivatives of 6- amino-penam-IS-carboxylic acid or 7-amino-ceph(3)em-4- carboxylic acid compounds, such as the 2-chloroethylcarbamoyl, cyanoacetyl, phenylglycyl (optionally with a substituted amino group), 2-thienylacetyl, 0t-amlH-2 thienylacetyl (optionally with a substituted amino group) or 1-arninocyclohexylcarbonyl residue (optionally with a substituted amino group), or an acyl residue which is readily eliminable, especially under acid conditions, for example, by treatment with trifluoroacetic acid, or by reduction, for example, by treatment with zinc in the presence of aqueous acetic acid, such as the tret.butyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl residue, or the Z-brornoethoxycarbonyl residue which can be converted into the latter, and R, represents hydrogen or acetyloxy.

In 6-arnino penam-3-carboxylic acid 2-iodoethyl ester compounds or 7-amino-cephem-4-carboxylic acid 2-iodoethyl ester starting materials used according to the invention, reducible groups optionally present can, under the reaction conditions, simultaneously be converted into other groups by reduction.

The process also comprises those embodiments according to which starting materials are used in the form of derivatives or are formed during the reaction.

The present invention also comprises the new Z-X-ethyl esters, wherein X represents chloro or bromo, primarily iodo, of 6-amino penarn-3-carboxylic acid compounds or 7-amino-cephem-4-carboxylic acid compounds, especially the Z-X-ethyl esters of 6-N-R-amino-2-R -2-R -penam-3- carboxylic acids or l-oxides thereof, as well as of 7-N-R- amino-3-R -ceph(2)em-4-carboxylic acids or 7-N-R- amino-3-R -ceph(3 )em-4-carboxylic acids, in which R and R have the above given meaning, primarily Z-X-ethyl esters of 6-N-R-amino-2,2-dimethyl-penam-Z-carboxylic aicds or l-oxides thereof, as well as of 7-N-R-amino-3-R methyl-ceph(2)em4-carboxylic acids or 7-N-R'-3-R,,- methyl-ceph(3)em-4-carboxylic acids, wherein R and R have the abovementioned significance, andabove all 2-X-v ethyl esters of 6-N-R"-amino-2,2-dimethyl-penam-3-carboxylic acids or l-oxides thereof, as well as of 7-N-R"- amino-3-R,,'-methyl-ceph(2) em-4-carboxylic acids or 7-N- R"-amino-R,,'-methyl-ceph(3)em 4 carboxylic acids, wherein R" and R, have the above given meaning.

The invention is described in more detail in the following examples; temperatures are given in degrees centigrade.

. EXAMPLE 1 A mixture of 3.5 g. of penicillin V in 20 ml. of absolute acetonitrile, 20 ml. of Z-bromoethanol and 0.25 ml. of,

absolute pyridine is treated dropwise over the course of minutes with a solution of 2.3 g. of dicyclohexylcarbodiimide in ml. of acetonitrile, whilst stirring. After stirring for 48 hours, the mixture is filtered, the filter residue is washed with benzene and pentane and the filtrate is threetimes taken to dryness at 4050/ 11 mm. Hg, once with 100 ml. of toluene, and twice with 50 ml. of toluene. The residue is taken up in benzene and filtered. The filtrate is evaporated and the residue is chromatographed on 100 g. of silica gel. The 2-bromoethyl ester of penicillin V is eluted with 9:1- and 8:2-mixtures of benzene and ethyl acetate and further processed without purification.

. 12 Asolution of 0.53 g. of Z-bromoethyl ester of penicillin Y in 30ml. of absolute diethyl ether is slowly treated at 0 with a solution of 0.25 g. of 3-chloroperbenzoic acid strength) in 20 ml. of diethyl ether. The reaction mixture is allowed to stand for 1 6 hours at about 5 is then washed with 20 mlilof a saturated sodium hydrogen carbonate'solution, dried and evaporated under reduced pressure. The Z-bromoethyl ester of pencillin-v sulph oxide is thus obtained and is purified chromatography on silica gel.- I l j The penicillin-,V-sulphoxide Z-bro'moethyl ester can also be obta'ined byeste'rifying penicillin-Y-sulphoxide "with 2-b'romoethanol in thepresence'of dicycloliexylcarbodi imide, for example, according to. the process described abOveQ', Y A solution of 5 g. of 'penicillin-V-sulphoxide Z-bromoethyl ester in 250 ml.' of dimethylformamideis treated with 5 ml. of acetic acid anhydride; the mixture is heated for one hour at and is then evaporated to dryness under a. pressure of 1 mm. Hg. The residueis dissolved iri ml. of methylene chloride and washed three times with water. The organic phaseis dried and thenfevapo} rated, and the residueischromatographed on'200' got silica gel, 19:1-, 9:1-, 4:1- and 1:1-mixtures'of benzene and ethyl acetate being used for elution. The 3-m'ethyl-7- (N-phenyloxyacetyl-amino -ceph 3 )em-4-carboxylic acid 2'-bromoethyl ester is obtained from those fractions which in the ultraviolet absorption spectrum show a'h at about 268 mu. i A i A solution of 0.765 g. of the 3-methyl- 7-(N-phenyloxyacetylamino)-ceph(3)ern-4-carboxylic acid 2-bro'moethyl ester in 5 ml. of acetone is treated with 0.96 g. ofsodium iodide and stirred for 16 hours at 35; a fine white precipitate forms. At the end of the reaction time, the solvent is distilled ofi under reduced pressure and the residue is treated with 50 ml. of ethyl acetate and '10 ml. of water; the mixture is shaken and separatedZfThe' 3-methy1 7 (N-phenyloxyacetylamino) ceph(3)em-ficarboxylic acid 2-iodoethyl' ester is obtained item the organic phase after washing. I A solution of 0.68 g. of 3-methyl7-(N-phnyloriyace: tyl-amino)- ceph(3)ern-4-carboxylic acid '2-iodoethyl ester in 5 ml. of tetrahydrofuran isfr'nixed with 50 inl. of,90,% aqueousacetic acid and with 8 g. of zinc dust and stirred tor'45 minutes at 0-5?. The precipitateis filtered offand rinsed with a small amount of acetic acid; the filtrate is concentrated tofa'volume' of 10] m1. at 30 under reduced pressure, and diluted with 80 ml. of methylene chloride. The organic solution is repeatedlywashed' with waterand finally extracted twice with 20 ml. at a time of a cold 2 N aqueous sodium hydrogen carbonate solution. The basic extracts are acidified with citric acid at 0 and extracted with methylene chloride. After evaporation, the organic extracts yield 2-methyl-7 -(N-phenylgisr atiestyl-aminokcephfi em 4 carboxylic acid, MB;

EXAMPLE 2 A suspension, cooled; to 0, of 7.44 g. of the potassium salt of penicillin G in 30ml. of ac'etone is treated with 2.75 g." of-2-bromoethanol while stirring, followed by 3.6 g. of pyridine. A total of 2.8 g. of 'phosgeneis then introduced with the exclusion of moisture; the addi tion takes about 20 minutes and is carried out at 0 5.

. The mixture is stirred for 30 minutesand is then diluted treated with a solution of 0.5 g. of 3-.chloroperbenzoic acid in 40 ml. of diethyl ether; the mixture is allowed to stand for 20 hours at to and is then diluted with 60 ml. of methylene chloride. A total of 0.4 g. of sodium sulphite and 40 ml. of a saturated aqueous sodium hydrogen carbonate solution are added, and the mixture well shaken for 5 minutes. The organic phase is sepa rated, washed with water, dried and evaporated. The residue contains the penicillin-G-sulphoxide. 2-bromoethyl ester, which is purified by chromatography on silica gel and elution with mixtures of benzene and ethyl acetate.

Heating the penicillin-G-sulphoxide 2-bromoethyl ester with acetic'acid anhydride in dimethylfor'rnamide according to the process described in Example 1 yields the 3- methyl 7 (N-phenylacetylamino)-ceph(3)em-4-carboxylic acid 2-bromoethyl ester which is converted into the corresponding 2-iodoethyl ester by means of sodium iodide in acetone. The resulting 3-methyl-7-(N-phenylacetylamino)-ceph(3)em-4-carboxylic acid 2 iodoethyl ester is converted into the 3-methyl-7-(N-phenylacetylamino)-ceph(3)em-4-carboxylic acid by treatment with zinc dust in the presence of 90% aqueous acetic acid.

' EXAMPLE 3 A solution of 0.475 g. of absolute pyridine in 60 ml. of absolute 1,1,1-trichloroethane is warmed to 60 under a nitrogen atmosphere, 1.82 g. of 3-methyl-7-(N-phenyloxyacetyl-amino)-ceph(3)em 4 carboxylic acid 2 bromoethyl ester are then added and the mixture is immediately treated with 1.24 g. of phosphorus pentachloride with good stirring. The whole is stirred for 90 inutes at 60-65 and the yellow-brown solution is then cooled to about 10 and treated with 100 ml. of absolute methanol. The mixture is then allowed to stand for 2 hours at room temperature, ml. of water are added dropwise, and the pH-value is adjusted to 2.5 by adding a 2 N aqueous sodium hydroxide solution. After stirring for 30 minutes at room temperature, the pH-value is adjusted to 7.0 by further addition of the sodium hydroxide solution, and the bulk of the solvent is removed under reduced pressure. The concentrated solution, which contains a precipitated oil, is extracted with ethyl acetate; the organic extracts are washed with three portions of distilled water and the aqueous phases are twice extracted with a small amount of ethyl acetate. The combined organic solutions are dried over magnesium sulfate and evaporated under reduced pressure. The oily slightly yellow residue represents the 7ramino-3-methylceph(3)em-4-carboxylic acid 2-bromoethyl ester, which in the infrared absorption spectrum (in methylene chloride) shows an intensive band at 5.66;; and which, according to thin layer chromatogram (silica gel plates; system: toluene/ethyl acetate 1:1) is homogeneous; it is used without further purification.

A mixture of 1.19 g. of the 7-amino-3-methyl-ceph(3)- em-4-carboxylic acid Z-bromoethyl ester and 100 ml. of absolute methylene chloride is cooled to 10 and treated with 1.38 g. of D-(-)-N-(2,2,2 trichloroethoxy car- -bonyl)-phenylglycyl chloride in 10 ml. of anhydrous methylene chloride. A mixture of 0.5 g. of N-ethyl-N,N- diisopropylamine in 10 ml. of absolute methylene chloride is added dropwise over the course of about 15 minutes; the mixture is allowed to warm to 0 and the reaction is completed in the course of 3 hours. After completion of the reaction, 40 ml. of distilled water are added while stirring, the layers are separated and the organic phase is extracted with two portions (30 ml. each) of each of a l-molar aqueous citric acid solution, an 0.1-molar aqueous dipotassium hydrogen phosphate solution and distilled water; the aqueous phases are each extracted with 50 ml. of methylene chloride. The combined organic solutions are dried over sodium sulfate and the solvent is removed under waterpum-p vacuum. The yellow-colored crude product is filtered through a silica gel column and the filtrate is evaporated. The 3-methyl-7-N-[N-(2,2,2-trichloroethoxy-carbonyl)-D phenylglycyl]-aminoceph(3)'em-4 carboxylic acid 2-bromoethyl ester is thus obtained in the form of an almost colorless foam, which in the infrared absorption spectrum (in methylene chloride) shows a characteristic band at 5.67, and which according to a thin layer chromatogram (silica gel plates; system: toluene/acetone 4:1) represents a homogeneous substance.

7 1.6 g. of 3-methyl-7-N-[N-(2,2,2-trichloroethoxy-carbonyl)-D-(--) phenylglycyl] amino ceph(3)em-4- carboxylic acid 2-brom oethyl ester are treated with a solution of 1.55 g. of sodium iodide in 7.8 ml. of purified acetone and the mixture is left to stand for 16 hours at 30 under a nitrogen atmosphere. The solvent is evaporated under reduced pressure and the residue is taken up in 30 ml. of water and 100 ml. of ethyl acetate and well shaken. The organic phase is dried under anhydrous sodium sulfate and evaporated to yield the 3-methyl-7-N-[N- (2,2,2-trichloroethoxy carbonyl) D phenylglycyl] amino ceph(3)em 4 carboxylic acid 2- iodoethyl ester as the residue, which is further processed without purification. v

A solution of 1.75 g. of 3-methyl-7-N-[N-(2,2,2-trichloroethoxy carbonyl) D phenylglycyl]- amino ceph(3)em 4 carboxylic acid 2-iodoethyl ester in 8 ml. of tetrahydrofuran is mixed with ml. of aqueous acetic acid cooled to 0 and treated with 10.5 g. of zinc dust. The reaction mixture is stirred for 1 hour (ultrasonic), filtered through a diatomaceous earth preparation (Celite), and the residue is extracted with 30 ml. of aqueous acetic acid (90%) and 30 ml. of tetrahydrofuran. The combined filtrates are evaporated under reduced pressure and the residue is mixed with 50 ml. of distilled water, then covered with ml. of methylisobutyl-ketone and acidified to pH 1 with trifluoroacetic acid while cooling with ice. The mixture is well shaken, the layers are separated and the aqueous phase is twice washed with methyl isobutyl ketone. The organic solutions are washed with a small amount of water, dried over magnesium sulfate and evaporated. The residue, which is repeatedly digested with absolute diethyl ether, represents the trifiuoracetate of 3-methyl-7-N [D phenylglycyl]-amino-ceph(3)em-4-carboxylic acid.

A solution of 0.46 g. of the crude trifluoroacetate of 3 methyl 7 N [D phenylglycyl] aminoceph(3)em 4 carboxylic acid in 2.5 ml. of ice-cooled 0.5-molar aqueous hydrochloric acid is extracted three times with 10 ml. of ethyl acetate at a time. The organic phases are extracted three times with 5 ml. of water at a time and discarded. The combined aqueous solutions are filtered and adjusted to pH 4 by adding a 2-molar aqueous ammonia solution, while cooling with ice. The suspended, finely crystalline material is filtered off, washed with a small amount of ice-water, cooled ethanol and diethyl ether, and dried in a high vacuum. The inner salt of 3- methyl 7 N [D phenylglycyl] amino-ceph (3)em-4-carboxylic acid is thus obtained, which shows the following Rf-values in a thin layer chromatogram (silica gel plates; development with iodine or ninhydrin/ collidine) :Rf=0.08 (system ethyl acetate/pyridine/acetic acid/ water 62:21:6z11; ninhydrin/collidine: ochre to red brown); Rf'=0.3 (system n-butanol/acetic acid/water 67: 10:23; ninhydrin/collidine: ochre to brown); Rf=0.2 (system ethyl acetate/n-butanol/pyridine/acetic acid/ water 42:21:2116zl0; ninhydrin/collidine: blue violet); Rf =0.5 and (system n-butanol/pyridine/acetic acid/ water 38:24:8z30; ninhydrin/collidine: ochre to brown); ultraviolet absorption spectrum (distilled water): X 262 mu (e=7400); [a] l- 114i1 (c.=0.863 in 50% aqueous acetonitrile) What is claimed is:

1. The 2-X-ethy1 ester of a member selected from the group consisting of a 7 N R amino-3-R -methyl-ceph (2)em-4-carboxylic acid and a 7-N-R-amino-3-R -methylceph(3)em-4-carboxylic acid, in which R represents a member selected from'ithe'wgronp consisting" ,of, hydrogen, p y w y 'y yl ph' fiy ly y h t i'l ya li ihienylacetyl, a-aminmthienylacjetyl, .g-amin -cycl'Qh'efxyl-j' ca rbonyl, and vN 2-chloroethyl-carbamyl, and a, lowef allgoxyca bonyl group, R stands for a member selected from the' group consisting of hydrogen, hydroxy, l ogve alkoxyand lower alkeinoyloxy, and X stands" for i051 o b f N n 2. A componnd as claimed in clfaim' l'and being the 2 X-ethyl ester of Ta member selected from the gro'upcon s'isting of a J N-R"amino-3 R;f-methy1-.ceph (2)'en1-4= cglrboxylic acid and. a 7 N ,-R"-amino-3-R '-methy1-cepli 3)em-4-carboxylic acid, wherein R" represents a mem: brfselected from the group consisting of hydrogen fi phenylacetyl, cyano acetyl, phenylglycyl, ihenyl'oxyac etyl; thienylacetyl, 'a am'ino-ihienylacetyl, a-amifioQcyclohexyH carbonyl, and N-Z-chloro'ethyl-cQrbamyl,f and a 10Wer alkoxy carbonyl group, R i represents hydrogen and acetyl'oxy and X is iodo'or-b romo'g V I 3. A compound as cla iined in clainll and being a riiern ber selected from the group consisting "ofifi-nxelhyl l -N- phenyloxy acetyl a n ino-cephfi)eni-4-cafbok'ylic' Acid Z-bfomothyljester and 3-methy1-7-N-phenylogyacetylamino-ceph(3') em-4-carboxylic acid 2-iodoethyl este 4. A compound as claimed in claim 1 and being a member selected from the group consisting of 3-methyl-7-N 

